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      Pleiotropic Mechanisms Indicated for Sex Differences in Autism

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          Abstract

          Sexual dimorphism in common disease is pervasive, including a dramatic male preponderance in autism spectrum disorders (ASDs). Potential genetic explanations include a liability threshold model requiring increased polymorphism risk in females, sex-limited X-chromosome contribution, gene-environment interaction driven by differences in hormonal milieu, risk influenced by genes sex-differentially expressed in early brain development, or contribution from general mechanisms of sexual dimorphism shared with secondary sex characteristics. Utilizing a large single nucleotide polymorphism (SNP) dataset, we identify distinct sex-specific genome-wide significant loci. We investigate genetic hypotheses and find no evidence for increased genetic risk load in females, but evidence for sex heterogeneity on the X chromosome, and contribution of sex-heterogeneous SNPs for anthropometric traits to ASD risk. Thus, our results support pleiotropy between secondary sex characteristic determination and ASDs, providing a biological basis for sex differences in ASDs and implicating non brain-limited mechanisms.

          Author Summary

          Autism Spectrum Disorders (ASDs) make up a debilitating neurodevelopmental disorder class. It has been known for a long time that more males than females are affected, but despite much speculation there is no clear etiological reason for this sex bias. As ASDs are highly heritable, we examined evidence in single nucleotide polymorphism (SNP) data for five plausible genetic models that could generate sex bias. We identified distinct genome-wide significant loci in each sex-specific dataset, and evaluated support in five analyses: 1) In contrast to rare variant contribution, we find no evidence for increased SNP genetic load in females. 2) Sex-heterogeneity is demonstrated on the X-chromosome. 3) We uncover no evidence for hormone-responsive genes being overrepresented in association signals. 4) We identify no signature for genes differentially brain-expressed between males and females contributing to ASDs. 5) We observe a strong signal of excess association in the same regions of the genome showing sex-heterogeneity in anthropometric traits. This latter finding is striking, implicating general sexual dimorphism as opposed to brain- or behavior-specific origins for sex differences contributing to ASDs.

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          Most cited references47

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          Advances in autism genetics: on the threshold of a new neurobiology.

          Autism is a heterogeneous syndrome defined by impairments in three core domains: social interaction, language and range of interests. Recent work has led to the identification of several autism susceptibility genes and an increased appreciation of the contribution of de novo and inherited copy number variation. Promising strategies are also being applied to identify common genetic risk variants. Systems biology approaches, including array-based expression profiling, are poised to provide additional insights into this group of disorders, in which heterogeneity, both genetic and phenotypic, is emerging as a dominant theme.
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            Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.

            Many studies have supported a genetic etiology for autism. Here we report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism.
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              The future of genetic studies of complex human diseases.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                15 November 2016
                November 2016
                : 12
                : 11
                : e1006425
                Affiliations
                [1 ]Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, California, United States of America
                [2 ]Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
                [3 ]Division of Research, Kaiser Permanente Northern California, California, United States of America
                [4 ]Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America
                [5 ]Université Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, France
                [6 ]Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America
                [7 ]Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, United States of America
                [8 ]Program in Developmental Neurogenetics, Institute for the Developing Mind, Children’s Hospital Los Angeles and Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
                [9 ]Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America
                [10 ]Department of Psychiatry and Behavioral Sciences, Medicine and Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute, University of California, Davis School of Medicine, Sacramento, California, United States of America
                [11 ]Department of Public Health Sciences and Medicine and Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute, University of California, Davis School of Medicine, Sacramento, California, United States of America
                [12 ]Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
                The Wellcome Trust Centre for Human Genetics, University of Oxford, UNITED KINGDOM
                Author notes

                The authors have declared that no competing interests exist.

                • Conceptualization: LAW.

                • Formal analysis: IM KT CLA MT AL.

                • Funding acquisition: LAW.

                • Investigation: KT.

                • Methodology: NZ MCO LAW.

                • Project administration: LAW.

                • Resources: LAC KAA RLH PL SN DGA IHP MDF.

                • Supervision: LAW.

                • Visualization: IM MT.

                • Writing – original draft: IM LAW.

                • Writing – review & editing: IM KT CLA LAC KAA RLH MT AL NZ MCO PL SN DGA IHP MDF LAW.

                Author information
                http://orcid.org/0000-0002-9882-3165
                http://orcid.org/0000-0002-3727-9530
                http://orcid.org/0000-0001-6952-2390
                http://orcid.org/0000-0002-5700-135X
                Article
                PGENETICS-D-16-01246
                10.1371/journal.pgen.1006425
                5147776
                27846226
                03ccbbdd-63f5-44e4-ab96-2a78de8c22f2
                © 2016 Mitra et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 June 2016
                : 12 October 2016
                Page count
                Figures: 3, Tables: 4, Pages: 27
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100006955, Office of Extramural Research, National Institutes of Health;
                Award ID: HD065273
                Award Recipient :
                Funded by: Simons Foundation Autism Research Initiative
                Award ID: 136720
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100006932, International Mental Health Research Organization;
                Award Recipient :
                Funded by: Department of Medicine, University of California, San Francisco (US)
                Award Recipient :
                We acknowledge funding sources NIH Exploratory/Developmental Research Grant Award (R21) HD065273 (LAW), Simons Foundation Autism Research Initiative (SFARI) 136720 (LAW) as well as IMHRO and UCSF-Research Evaluation and Allocation Committee (REAC) support (LAW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Chromosome Biology
                Chromosomes
                Sex Chromosomes
                X Chromosomes
                Biology and Life Sciences
                Psychology
                Developmental Psychology
                Autism Spectrum Disorder
                Autism
                Social Sciences
                Psychology
                Developmental Psychology
                Autism Spectrum Disorder
                Autism
                Biology and Life Sciences
                Neuroscience
                Developmental Neuroscience
                Neurodevelopmental Disorders
                Autism
                Medicine and Health Sciences
                Neurology
                Neurodevelopmental Disorders
                Autism
                Biology and Life Sciences
                Genetics
                Genetic Loci
                Biology and Life Sciences
                Genetics
                Heredity
                Genetic Load
                Biology and Life Sciences
                Developmental Biology
                Morphogenesis
                Sexual Differentiation
                Sexual Dimorphism
                Social Sciences
                Anthropology
                Physical Anthropology
                Anthropometry
                Biology and Life Sciences
                Physical Anthropology
                Anthropometry
                Biology and Life Sciences
                Computational Biology
                Genome Analysis
                Genome-Wide Association Studies
                Biology and Life Sciences
                Genetics
                Genomics
                Genome Analysis
                Genome-Wide Association Studies
                Biology and Life Sciences
                Genetics
                Human Genetics
                Genome-Wide Association Studies
                Physical Sciences
                Mathematics
                Discrete Mathematics
                Combinatorics
                Permutation
                Custom metadata
                All UCSF ASD genotype data are available from the The National Database for Autism Research (NDAR) under accession number 1883 for researchers that meet requirements for access. Previously published GWAS data include Autism Genetic Resource Exchange (AGRE)-Weiss ( http://agre.autismspeaks.org/site/c.lwLZKnN1LtH/b.5332889/k.B473/AGRE.htm), AGRE- Wang ( http://agre.autismspeaks.org/site/c.lwLZKnN1LtH/b.5332889/k.B473/AGRE.htm, Simons Simplex Collection (SSC) ( http://sfari.org/resources/autism-cohorts/simons-simplex-collection), Autism Genome Project (AGP) ( http://www.autismspeaks.org/science/initiatives/autism-genome-project), and Early Markers for Autism (EMA) (Tsang KM, Croen LA, Torres AR, Kharrazi M, Delorenze GN, Windham GC, Yoshida CK, Zerbo O, Weiss LA. (2013) A genome-wide survey of transgenerational genetic effects in autism. PLoS One. 2013 Oct 24;8(10):e76978. doi: 10.1371/journal.pone.0076978.)

                Genetics
                Genetics

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